1. Field of the Invention
The present invention relates to pharmaceutical compositions, for hepatic disorders, comprising triterpene derivatives or salts thereof as an active ingredient. The present invention also relates to novel triterpene derivatives.
2. Background Art
A liver is an important organ which has various functions necessary for maintaining life of a living body, such as detoxication, various metabolisms, and storage of substances. It, however, often undergoes acute or chronic damage due to viruses, drugs, alcohols and other various causes. This induces viral hepatitis, drug-induced hepatopathy, alcoholic hepatopathy, fatty liver, and, in addition, diseases such as cirrhosis and hepatic cancer.
For treating such hepatic diseases, alimentary therapy, rest cure, and other therapies using glycyrrhizin preparations, adrenocortical steroids, interferon and the like have hitherto been employed. These therapies, however, cannot be said to be satisfactorily effective for the treatment of hepatic disorders. Glycyrrhizin and interferon are intravenously administered and, hence, unsuitable for prolonged administration. Further, the interferon and steroids have a problem of side effect.
Some triterpene derivatives have anticomplementary activity and platelet aggregation inhibitory activity. Thus, they and are known as prophylactic and pharmaceutical compositions for immunological diseases and thrombosis (Japanese Patent Laid-Open No. 85344/1986). However, there is no report which discloses that the triterpene derivatives are effective as a pharmaceutical composition for treating hepatic disorders.
The present inventors have now found that certain triterpene derivatives are effective for treating hepatic disorders. Further, they have succeeded in synthesis of novel triterpene derivatives. The present invention has been made based on such novel finding.
According to the first aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder comprising as an active ingredient a triterpene derivative represented by the following formula (I) or a salt thereof: 
wherein
R1 represents
a hydroxyl group,
arylmethyl oxy,
lower alkoxy, or
lower alkanoyloxy;
R2 represents
lower alkyl,
lower alkenyl,
xe2x80x94CH2OR5 wherein R5 represents a hydrogen atom, arylmethyl, lower alkyl, or lower alkanoyl,
formyl,
xe2x80x94COOR6 wherein R6 represents a hydrogen atom or lower alkyl, or
xe2x80x94CH2N(R7)R8 wherein R7 and R8, which may be the same or different, represent a hydrogen atom, lower alkyl, aryl, or lower alkanoyl;
or R1 and R2 may combine with each other to form xe2x80x94Oxe2x80x94C(R9)R10xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein R9 and R10, which may be the same or different, represent a hydrogen atom, lower alkyl, or aryl;
R3 and R4, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
lower alkyl,
lower alkenyl,
aryl,
hydroxymethyl,
xe2x80x94N(R11)R12 wherein R11 and R12, which may be the same or different, represent a hydrogen atom, lower alkyl, or lower alkanoyl,
formyl,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94OR13 wherein R13 represents lower alkyl, cyclo-lower alkyl, aralkyl, lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, lower alkenylcarbonyl, or aryl-lower alkenylcarbonyl;
or R3 and R4 may combine with each other to form oxo, hydroxyimino, or alkylidene; and
X represents O, CH2, or NH.
According to the second aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (II) or a salt thereof: 
wherein
R16 represents
a hydroxyl group,
arylmethyloxy,
lower alkoxy, or
lower alkanoyloxy;
R17 represents
lower alkyl,
lower alkenyl
xe2x80x94CH2OR5 wherein R5 is as defined above,
formyl,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94CH2OCON(R9)R10 wherein R9 and R10 are as defined above,
xe2x80x94CON(R29)R30 wherein R29 and R30, which may be the same or different, represent a hydrogen atom, lower alkyl, lower alkanoyl, aryl, or aralkyl;
xe2x80x94CH2N(R7)R8 wherein R7 and R8 are as defined above;
xe2x80x94C(R6)2OH wherein R6 is as defined above;
xe2x80x94COR6 wherein R6 is as defined above;
xe2x80x94CHxe2x95x90CHR6 wherein R6 is as defined above;
or R16 and R17 may combine with each other to form xe2x80x94Oxe2x80x94C(R9)R10xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein R9 and R10 are as defined above;
R18 and R19, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
arylmethyloxy,
lower alkyl,
xe2x80x94N(R11)R12 wherein R11 and R12 are as defined above,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94OR13 wherein R13 is as defined above,
xe2x80x94Oxe2x80x94( CH2)mxe2x80x94R22 
wherein
R22 represents
amino,
xe2x80x94NHxe2x80x94COOR23 wherein R23 represents arylmethyl or lower alkyl,
a hydroxyl group,
arylmethyloxy, or
xe2x80x94COOR24 wherein R24 represents a hydrogen atom, lower alkyl, or arylmethyl, and
m is an integer of 1 to 4,
xe2x80x94OCOCH(R25)(CH2)nxe2x80x94R22 wherein R22 is as defined above, R25 represents a hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0 to 3,
xe2x80x94OCOCHxe2x95x90CHxe2x80x94COOR6 wherein R6 is as defined above, or xe2x80x94OCON(R29)R30 wherein R29 and R30 are as defined above;
or R18 and R19 may combine with each other to form oxo,
R20 and R21 respectively represent the same meanings as R18 and R19, provided that R20 and R21 do not represent a hydrogen atom;
or R18 and R20 may combine with each other to form xe2x80x94Oxe2x80x94[C(R9)R10]pxe2x80x94Oxe2x80x94 wherein R9 and R10 are as defined above and p is an integer of 1 to 3, or xe2x80x94OCOxe2x80x94[C(R9)R10]qxe2x80x94OCOxe2x80x94 wherein R9 and R10 are as defined above and q is an integer of 0 to 2; and
Y represents O, CH2, NH, or a single bond to form a double bond in the ring with Y bonded thereto.
According to the third aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (III) or a salt thereof: 
wherein
R1, R2, and Y are as defined above; and
R27 represents
xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R22 wherein R22 and m are as defined above,
xe2x80x94OCOCH(R25)(CH2)nxe2x80x94R22 wherein R22, R25, and n are as defined above,
xe2x80x94OCON( R29 )R30 wherein R29 and R30 are as defined above,
xe2x80x94OCOxe2x80x94(CH2)nxe2x80x94R16 wherein R16 is as defined above, or
xe2x80x94OCOCHxe2x95x90CHxe2x80x94COOR6 wherein R6 is as defined above.
According to the fourth aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (IV) or a salt thereof: 
wherein
R1, R18, R19, and Y are as defined above; and
R28 represents
xe2x80x94CON(R29)R30 wherein R29 and R30 are as defined above,
xe2x80x94C(R6)2OH wherein R6 is as defined above,
xe2x80x94COR6a wherein R6a represents lower alkyl, or
xe2x80x94CHxe2x95x90CHR6 wherein R6 is as defined above.
The first group of novel compounds according to the present invention is triterpene derivatives represented by the following formula (Ia) or salts thereof: 
wherein
R1 represents a hydroxyl group, lower alkoxy, or lower alkanoyloxy;
R2 represents hydroxymethyl, lower alkoxymethyl, lower alkanoyloxymethyl, or carboxyl;
or R1 and R2 may combine with each other to form xe2x80x94Oxe2x80x94C(R14)R15xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein R14 and R15, which may be the same or different, represent a hydrogen atom or lower alkyl;
R3 and R4, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
lower alkyl,
lower alkenyl,
aryl,
hydroxymethyl,
xe2x80x94N(R11)R12 wherein R11 and R12, which may be the same or different, represent a hydrogen atom, lower alkyl, or lower alkanoyl,
formyl,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94OR13 wherein R13 represents lower alkyl, cyclo-lower alkyl, aralkyl, lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, lower alkenylcarbonyl, or aryl-lower alkenylcarbonyl;
or R3 and R4 may combine with each other to form oxo, hydroxyimino, or alkylidene; and
X represents O, CH2, or NH, provided that compounds wherein R1 represents a hydroxyl group, R2 represents hydroxymethyl, R3 represents a hydrogen atom, R4 represents a hydroxyl group and X represents O are excluded.
The second group of novel compounds according to the present invention is triterpene derivatives represented by the following formula (IIa) or salts thereof: 
wherein
R16 represents
a hydroxyl group,
arylmethyloxy,
lower alkoxy, excluding methoxy, or
lower alkanoyloxy, excluding acetoxy;
R17 represents
lower alkyl,
lower alkenyl
xe2x80x94CH2OR5 wherein R5 is as defined above,
formyl,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94CH2OCON(R9)R10 wherein R9 and R10 are as defined above,
xe2x80x94CON(R7)R8 wherein R7 and R8 are as defined above,
xe2x80x94CH2N(R7)R8 wherein R7 and R8 are as defined above,
xe2x80x94C(R6)2OH wherein R6 is as defined above,
xe2x80x94COR6a wherein R6a represents lower alkyl, or
xe2x80x94CHxe2x95x90CHR6 wherein R6 is as defined above;
or R16 and R17 may combine with each other to form xe2x80x94Oxe2x80x94C(R9)R10xe2x80x94Oxe2x80x94CH2xe2x80x94 wherein R9 and R10 are as defined above;
R18 and R19, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
arylmethyloxy,
lower alkyl,
xe2x80x94N(R11)R12 wherein R11 and R12 are as defined above,
xe2x80x94COOR6 wherein R6 is as defined above,
xe2x80x94OR13 wherein R13 is as defined above,
xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R22 
wherein
R22 represents
amino,
xe2x80x94NHxe2x80x94COOR23 wherein R23 represents arylmethyl or lower alkyl,
a hydroxyl group,
arylmethyloxy, or
xe2x80x94COOR24 wherein R24 represents a hydrogen atom, lower alkyl, or arylmethyl, and
m is an integer of 1 to 4,
xe2x80x94OCOCH(R25)(CH2)nxe2x80x94R22 wherein R22 is as defined above, R25 represents a hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0 to 3,
xe2x80x94OCOCHxe2x95x90CHxe2x80x94COOR6 wherein R6 is as defined above, or xe2x80x94OCON(R29)R30 wherein R29 and R30 are as defined above;
or R18 and R19 may combine with each other to form oxo,
R20 and R21 respectively represent the same meanings as R18 and R19, provided that R20 and R21 do not represent a hydrogen atom;
or R18 and R20 may combine with each other to form xe2x80x94Oxe2x80x94[C(R9)R10]pxe2x80x94Oxe2x80x94 wherein R9 and R10 are as defined above and p is an integer of 1 to 3, or xe2x80x94OCOxe2x80x94[C(R9)R10]qxe2x80x94OCOxe2x80x94 wherein R9 and R10 are as defined above and q is an integer of 0 to 2; and
Y represents O, CH2, NH, or a single bond to form a double bond in the ring with Y bonded thereto;
provided that compounds wherein R16 represents a hydroxyl group, R17 represents xe2x80x94CH2OCH3, R20 represents a hydroxyl group or methoxy, both R18 and R21 represent a hydrogen atom, R19 represents a hydroxyl group or methoxy and Y represents a single bond, and compounds wherein R16 represents a hydroxyl group, R17 represents xe2x80x94CH2OH, R20 represents a hydroxyl group, R18, R19, and R21 represent a hydrogen atom and Y represents a single bond are excluded.
The third group of novel compounds according to the present invention is compounds represented by the formula (III).
The fourth group of novel compounds according to the present invention is compounds represented by the formula (IV).